Abstract
Sophocarpine is the major pharmacologically active compound of the traditional Chinese herbal medicine Radix Sophorae Subprostratae which has been used in treating hepatitis for years in China. It has been demonstrated that Sophocarpine exerts an activity in immune modulation and significantly decreases the production of inflammatory cytokines. However, the protective effects of Sophocarpine in T cell-dependent immune hepatitis remained unknown. The aim of this study was to determine the protective effects and pharmacological mechanisms of Sophocarpine on Concanavalin A (ConA)-induced hepatitis, an experimental model of T cell-mediated liver injury. BALB/C mice were pretreated with Sophocarpine or Bicyclol for five consecutive days. Thirty minutes after the final administration, the mice were injected with 15 mg⋅kg-1 of ConA intravenously. The results indicated that pretreatment with Sophocarpine significantly ameliorated liver inflammation and injury as evidenced by both biochemical and histopathological observations. Moreover, in Sophocarpine-pretreated mice, liver messenger RNA expression levels of chemokines and adhesion molecules, such as macrophage inflammatory protein-1α, CXC chemokine ligand 10, and Intercellular adhesion molecule-1, were markedly reduced. Further studies revealed that Sophocarpine significantly downregulated the expression of T-bet via inhibition of signal transducers and activators of transcription1 (STAT1) activation and overexpression of suppressor of cytokine signaling1, inhibiting the activation of Th1 cells and the expression of Interferon-γ (IFN-γ). Altogether, these results suggest new opportunities to use Sophocarpine in the treatment of T cell-mediated liver disease. In summary, Sophocarpine could attenuate ConA-induced liver injury, and the protective effect of Sophocarpine was associated with its inhibition effect of pro-inflammatory cytokines, chemokines, and the IFN-γ/STAT1 signaling pathway.
Highlights
Hepatitis, which is caused by alcohol drinking, certain drugs, viral infection, or autoimmunity, is a serious threat to human health (Zheng et al, 2016)
Administration of Bicyclol and Sophocarpine inhibited the elevation of alanine aminotransferase (ALT) [Bicyclol: 628.12 ± 205.94, Sophocarpine (30 mg·kg−1): 398.02 ± 178.35, Sophocarpine (60 mg·kg−1): 171.25 ± 113.68], aspartate aminotransferase (AST) [Bicyclol: 219.81 ± 83.58, Sophocarpine (30 mg·kg−1): 157.69 ± 59.55, Sophocarpine (60 mg·kg−1): 84.46 ± 25.28], and total bilirubin (TBIL) [Bicyclol: 5.08 ± 1.13, Sophocarpine (30 mg·kg−1): 5.05 ± 1.42, Sophocarpine (60 mg·kg−1): 3.21 ± 1.25] compared with the Concanavalin A (ConA) group (Figures 1A–C)
Sophocarpine is a quinolizidine alkaloid extracted from Radix Sophorae Subprostratae a traditional Chinese herb that has been widely used in the treatment of liver diseases for years in China
Summary
Hepatitis, which is caused by alcohol drinking, certain drugs, viral infection, or autoimmunity, is a serious threat to human health (Zheng et al, 2016). ConA-induced autoimmune hepatitis has been widely used in studies of immune hepatitis treatment in humans which has been considered a well-established experimental model for immune-mediated liver injury. CD4 T cells were essential to mediate adaptive immunity in response to a variety of pathogens. In the pathogenesis of ConA injection, IFN-γ was reported to be critically involved in liver injury because in the mice deficient in IFN-γ or treated with IFN-γ–neutralizing monoclonal antibody its disease progress was significantly reduced (Miyagi et al, 2004). IFN-γ was reported to activate STAT1, inducing T-bet expression, which is essential for Th1 cell differentiation (Shinohara et al, 2005; Zhu et al, 2010). It has been reported that overexpression of SOCS1 prevents ConA-induced liver injury by suppressing STAT1 activation (Ogata et al, 2006)
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